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Stanton was born in Irvine, Kentucky, the son of Sheridan Harry Stanton, a tobacco farmer and barber, and Ersel (née Moberly), a hair dresser.[2][3] His parents divorced when Stanton was in high school and both later remarried.[citation needed] He has two younger brothers, Archie and Ralph, and a younger half-brother, Stan. The family had a musical background. Stanton attended Lafayette High School and the University of Kentucky in Lexington where he performed at the Guignol Theatre under the direction of UK theater icon Wallace Briggs[4] and studied journalism and radio arts. "I could have been a writer," he told an interviewer for a 2011 documentary, Harry Dean Stanton: Crossing Mulholland, in which he sings and plays the harmonica.[5] "I had to decide if I wanted to be a singer or an actor. I was always singing. I thought if I could be an actor, I could do all of it." Briggs encouraged him to leave the university and become an actor. He studied at the Pasadena Playhouse in Pasadena, California, where his classmates included his friends Tyler MacDuff and Dana Andrews.

His breakthrough part[7] came with the lead role in director Wim Wenders' film Paris, Texas (1984). Playwright Sam Shepard, the movie's screenwriter had spotted Stanton at a Santa Fe, New Mexico bar in 1983 while both were attending a film festival in that city, and the two fell into conversation. "I was telling him I was sick of the roles I was playing," Stanton recalled in a 1986 interview. "I told him I wanted to play something of some beauty or sensitivity. I had no inkling he was considering me for the lead in his movie."[7] Not long afterward, Shepard phoned him in Los Angeles to offer Stanton the part of protagonist Travis,[7] "a role that called for the actor to remain largely silent ... as a lost, broken soul trying to put his life back together and reunite with his estranged family after having vanished years earlier."[8]

Stanton was a favorite of the late film critic Roger Ebert who has said that "no movie featuring either Harry Dean Stanton or M. Emmet Walsh in a supporting role can be altogether bad." However, Ebert later admitted that Dream a Little Dream (1989), in which Stanton appeared, was a "clear violation" of this rule.[9]

The second annual Harry Dean Stanton Film Festival was held over a weekend in May 2012 at the Kentucky Theater and other venues in downtown Lexington. Festival co-producer Lucy Jones[12] visited with Stanton in California and brought back a filmed greeting for the festival, with introductions to the films and talk about films he was working on.[4]

Stanton is the subject of a 2013 documentary titled Harry Dean Stanton: Partly Fiction, directed by Sophie Huber and featuring film clips; interviews with collaborators including Wenders, Shepard, Kris Kristofferson, and David Lynch; and Stanton's singing.[13]

The May 2013 Stanton festival in Lexington included an appearance by Crispin Glover, a co-star with Stanton in Wild at Heart, the 1989 comedy Twister and the Lynch-directed HBO original series Hotel Room in 1993; and a pre-release screening of the Partly Fiction.[14]